A range of different approaches have been used for modifying the structure of therapeutical peptides such as GLP-1 and exendin-4 in order to provide a longer duration of action in vivo. For example, WO 2006/097538, WO 2006/097536, WO 2006/037810, WO2006005667, WO 2005/027978. WO 98/08871 and US 2001/0011071 describe various GLP-1 analogues and derivatives thereof.
Many diabetes patients particularly in the type 2 diabetes segment are subject to so-called “needle-phobia”, i.e. a substantial fear of injecting themselves. In the type 2 diabetes segment most patients are treated with oral hypoglycaemic agents, and since GLP-1 compounds are expected to be an injectable pharmaceutical product these patients will be administered, the fear of injections may become a serious obstacle for the widespread use of the clinically very promising compounds. Thus, there is a need to develop new compounds which can be administered less than once daily, e.g. once every second or third day preferably once weekly, while retaining an acceptable clinical profile or optionally via non invasive administration such as pulmonary, nasal, sublingual, bucal or oral administration.
One object of the invention is to provide long acting, i.e. having an administration regimen as described above, peptide derivatives, such as derivatives of GLP-1, exendin-4, or analogues thereof.
Another object of this invention is to provide peptide derivatives such as derivatives of GLP-1, exendin-4, or analogues thereof with high potency (receptor affinity) in order to reduce the therapeutic dose used for example for once weekly s.c. dosing or alternatively for non-invasive delivery.
A further object is to provide derivatives of GLP-1 or analogues thereof for which the affinity to the GLP-1 receptor is only partly decreased when comparing the affinity in the presence of very low concentration of human albumin to the affinity in the presence of a higher concentration of human albumin. The shift in binding affinity is preferably low.
Another object of this invention is to provide peptide derivatives such as derivatives of GLP-1 or analogues thereof with high albumin binding affinity which protects the peptide for proteolytic degradation and reduce renal clearance of the peptide.
Potency, in particular the ratio of binding affinity to the GLP-1 receptor in the presence of low and high albumin concentrations, half-life, and binding affinity to albumin are properties of potential relevance for an overall object of achieving long-acting, stable and of course therapeutically active peptide derivatives such as GLP-1 derivatives with a potential for once weekly administration.
The peptide derivatives of the invention are preferably chemically, physically and enzymatically stable.